{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,28]],"date-time":"2026-01-28T20:58:50Z","timestamp":1769633930797,"version":"3.49.0"},"reference-count":47,"publisher":"Elsevier BV","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/tdm\/userlicense\/1.0\/"},{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.elsevier.com\/legal\/tdmrep-license"},{"start":{"date-parts":[[2021,7,25]],"date-time":"2021-07-25T00:00:00Z","timestamp":1627171200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["NNF16OC0021948"],"award-info":[{"award-number":["NNF16OC0021948"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","award":["115363"],"award-info":[{"award-number":["115363"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["NNF16OC0021948"],"award-info":[{"award-number":["NNF16OC0021948"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010767","name":"Innovative Medicines Initiative","doi-asserted-by":"publisher","award":["115363"],"award-info":[{"award-number":["115363"]}],"id":[{"id":"10.13039\/501100010767","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elsevier.com","sciencedirect.com"],"crossmark-restriction":true},"short-container-title":["Journal of Controlled Release"],"published-print":{"date-parts":[[2021,10]]},"DOI":"10.1016\/j.jconrel.2021.07.030","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T17:06:11Z","timestamp":1626887171000},"page":"8-21","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":31,"special_numbering":"C","title":["Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin"],"prefix":"10.1016","volume":"338","author":[{"given":"Ragna Guldsmed","family":"Diedrichsen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stine","family":"Harloff-Helleberg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Werner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melissa","family":"Besenius","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ekkehard","family":"Leberer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mie","family":"Kristensen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanne M\u00f8rck","family":"Nielsen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"78","reference":[{"key":"10.1016\/j.jconrel.2021.07.030_bb0005","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1038\/nrd2399","article-title":"Protein therapeutics: a summary and pharmacological classification","volume":"7","author":"Leader","year":"2008","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0010","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/978-1-61779-921-1_1","article-title":"Therapeutic proteins","volume":"899","author":"Dimitrov","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0015","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1111\/bcpt.12515","article-title":"Cell-penetrating peptides as carriers for oral delivery of biopharmaceuticals","volume":"118","author":"Kristensen","year":"2016","journal-title":"Basic Clin. Pharmacol. Toxicol."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0020","series-title":"Cell-Penetrating Pept. Methods Protoc","first-page":"3","article-title":"Classes of cell-penetrating peptides","author":"Pooga","year":"2015"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0025","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1517\/17425247.5.1.105","article-title":"Cell-penetrating peptides for drug delivery across membrane barriers","volume":"5","author":"Foged","year":"2008","journal-title":"Expert Opin. Drug Deliv."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0030","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.jconrel.2008.08.001","article-title":"Usefulness of cell-penetrating peptides to improve intestinal insulin absorption","volume":"132","author":"Kamei","year":"2008","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0035","doi-asserted-by":"crossref","first-page":"10444","DOI":"10.1016\/S0021-9258(17)34080-2","article-title":"The third helix of the Antennapedia homeodomain translocates through biological membranes","volume":"269","author":"Derossi","year":"1994","journal-title":"J. Biol. Chem."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0040","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.jconrel.2014.06.022","article-title":"In vivo proof of concept of oral insulin delivery based on a co-administration strategy with the cell-penetrating peptide penetratin","volume":"189","author":"Nielsen","year":"2014","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0045","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1002\/jps.23364","article-title":"Determination of the optimal cell-penetrating peptide sequence for intestinal insulin delivery based on molecular orbital analysis with self-organizing maps","volume":"102","author":"Kamei","year":"2012","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0050","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1016\/j.jconrel.2010.01.019","article-title":"Structural requirements of penetratin absorption enhancement efficiency for insulin delivery","volume":"143","author":"Khafagy","year":"2010","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0055","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1208\/s12248-015-9747-3","article-title":"Penetratin-mediated transepithelial insulin permeation: importance of cationic residues and pH for complexation and permeation","volume":"17","author":"Kristensen","year":"2015","journal-title":"AAPS J."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0060","doi-asserted-by":"crossref","first-page":"738","DOI":"10.1096\/fj.12-216176","article-title":"Tryptophan within basic peptide sequences triggers glycosaminoglycan-dependent endocytosis","volume":"27","author":"Bechara","year":"2013","journal-title":"FASEB J."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0065","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.jconrel.2010.02.004","article-title":"Acylation of octaarginine: implication to the use of intracellular delivery vectors","volume":"149","author":"Katayama","year":"2011","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0070","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1016\/j.jconrel.2008.11.025","article-title":"A stearylated CPP for delivery of splice correcting oligonucleotides using a non-covalent co-incubation strategy","volume":"134","author":"M\u00e4e","year":"2009","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0075","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1016\/j.bbamem.2011.12.028","article-title":"Influence of stearyl and trifluoromethylquinoline modifications of the cell penetrating peptide TP10 on its interaction with a lipid membrane","volume":"1818","author":"Anko","year":"2012","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0080","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1016\/j.jcis.2020.05.121","article-title":"Shuffled lipidation pattern and degree of lipidation determines the membrane interaction behavior of a linear cationic membrane-active peptide","volume":"578","author":"Hedegaard","year":"2020","journal-title":"J. Colloid Interface Sci."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0085","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0109939","article-title":"Acylation of glucagon-like peptide-2: interaction with lipid membranes and in vitro intestinal permeability","volume":"9","author":"Trier","year":"2014","journal-title":"PLoS One"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0090","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.ejpb.2015.09.001","article-title":"Acylation of salmon calcitonin modulates in vitro intestinal peptide flux through membrane permeability enhancement","volume":"96","author":"Trier","year":"2015","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0095","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1046\/j.1464-5491.1999.00081.x","article-title":"Time-action profile of the soluble, fatty acid acylated, long-acting insulin analogue NN304","volume":"16","author":"Heinemann","year":"1999","journal-title":"Diabet. Med."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0100","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1111\/j.2042-7158.1992.tb05463.x","article-title":"Improvement of large intestinal absorption of insulin by chemical modification with palmitic acid in rats","volume":"44","author":"Hashizume","year":"1992","journal-title":"J. Pharm. Pharmacol."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0105","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1002\/jps.2600840604","article-title":"Absorption characteristics of chemically modified-insulin derivatives with various fatty acids in the small and large intestine","volume":"84","author":"Asada","year":"1995","journal-title":"J. Pharm. Sci."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0110","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0005-2736(85)90521-8","article-title":"Production of large unilamellar vesicles by a rapid extrusion procedure. Characterization of size distribution, trapped volume and ability to maintain a membrane potential","volume":"812","author":"Hope","year":"1985","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0115","doi-asserted-by":"crossref","first-page":"E3095","DOI":"10.1073\/pnas.1500851112","article-title":"Accurate secondary structure prediction and fold recognition for circular dichroism spectroscopy","volume":"112","author":"Micsonai","year":"2015","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0120","series-title":"Cell-Penetrating Pept. Methods Protoc","first-page":"249","article-title":"Cell-penetrating peptides as carriers for transepithelial drug delivery in vitro","author":"R\u00f8nholt","year":"2011"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0125","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/0022-1759(83)90303-4","article-title":"Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays","volume":"65","author":"Mosmann","year":"1983","journal-title":"J. Lmmunol. Methods."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0130","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.jpba.2014.01.022","article-title":"Insulin diffusion and self-association characterized by real-time UV imaging and Taylor dispersion analysis","volume":"92","author":"Jensen","year":"2014","journal-title":"J. Pharm. Biomed. Anal."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0135","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1016\/j.bbamem.2010.03.005","article-title":"Secondary structure of cell-penetrating peptides controls membrane interaction and insertion","volume":"1798","author":"Eir\u00edksd\u00f3ttir","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0140","doi-asserted-by":"crossref","first-page":"2876","DOI":"10.1038\/nprot.2006.202","article-title":"Using circular dichroism spectra to estimate protein secondary structure","volume":"1","author":"Greenfield","year":"2007","journal-title":"Nat. Protoc."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0145","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-24154-z","article-title":"Fluorophore labeling of a cell-penetrating peptide significantly alters the mode and degree of biomembrane interaction","volume":"8","author":"Hedegaard","year":"2018","journal-title":"Sci. Rep."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0150","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.jconrel.2009.02.015","article-title":"Importance of intermolecular interaction on the improvement of intestinal therapeutic peptide\/protein absorption using cell-penetrating peptides","volume":"136","author":"Kamei","year":"2009","journal-title":"J. Control. Release"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0155","doi-asserted-by":"crossref","first-page":"23910","DOI":"10.1039\/C7CP04320A","article-title":"Self-aggregation propensity of the tat peptide revealed by UV-vis, NMR and MD analyses","volume":"19","author":"Macchi","year":"2017","journal-title":"Phys. Chem. Chem. Phys."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0160","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep16914","article-title":"Spontaneous membrane- translocating peptides: influence of peptide self-aggregation and cargo polarity","volume":"5","author":"Macchi","year":"2015","journal-title":"Sci. Rep."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0165","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.ijpharm.2009.12.060","article-title":"The role of intermolecular interactions with penetratin and its analogue on the enhancement of absorption of nasal therapeutic peptides","volume":"388","author":"Khafagy","year":"2010","journal-title":"Int. J. Pharm."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0170","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1021\/bi3008609","article-title":"Ligand-controlled assembly of hexamers, dihexamers, and linear multihexamer structures by the engineered acylated insulin degludec","volume":"52","author":"Steensgaard","year":"2013","journal-title":"Biochemistry."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0175","series-title":"Cell-Penetrating Pept. Methods Mol. Biol","first-page":"29","article-title":"Penetratin story: An overview","author":"Dupont","year":"2015"},{"key":"10.1016\/j.jconrel.2021.07.030_bb0180","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/S0005-2736(01)00304-2","article-title":"Interaction and structure induction of cell-penetrating peptides in the presence of phospholipid vesicles","volume":"1512","author":"Magzoub","year":"2001","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0185","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/0300985814559404","article-title":"Epithelial cell shedding and barrier function: a matter of life and death at the small intestinal villus tip","volume":"52","author":"Williams","year":"2015","journal-title":"Vet. Pathol."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0190","first-page":"1404","article-title":"Redistribution of the tight junction protein ZO-1 during physiological shedding of mouse intestinal epithelial cells","volume":"300","author":"Guan","year":"2011","journal-title":"Am. J. Phys. Cell Phys."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0195","doi-asserted-by":"crossref","first-page":"75","DOI":"10.4155\/tde.10.5","article-title":"Restoration of rat colonic epithelium after in situ intestinal instillation of the absorption promoter, sodium caprate","volume":"1","author":"Wang","year":"2010","journal-title":"Ther. Deliv."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0200","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1038\/s41573-019-0053-0","article-title":"Advances in oral peptide therapeutics","volume":"19","author":"Drucker","year":"2020","journal-title":"Nat. Rev. Drug Discov."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0205","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s11095-007-9509-8","article-title":"Evaluation of mucosal damage and recovery in the gastrointestinal tract of rats by a penetration enhancer","volume":"25","author":"Narkar","year":"2008","journal-title":"Pharm. Res."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0210","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.aar7047","article-title":"Transcellular stomach absorption of a derivatized glucagon-like peptide-1 receptor agonist","volume":"10","author":"Buckley","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0215","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/pharmaceutics11020073","article-title":"Dual action of the PN159\/KLAL\/MAP peptide: increase of drug penetration across Caco-2 intestinal barrier model by modulation of tight junctions and plasma membrane permeability","volume":"11","author":"Bocsik","year":"2019","journal-title":"Pharmaceutics."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0220","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1021\/mp400493b","article-title":"Penetratin derivative-based nanocomplexes for enhanced intestinal insulin delivery","volume":"11","author":"Zhu","year":"2014","journal-title":"Mol. Pharm."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0225","doi-asserted-by":"crossref","DOI":"10.1080\/21688370.2016.1178369","article-title":"Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals","volume":"4","author":"Kristensen","year":"2016","journal-title":"Tissue Barriers."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0230","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.ejpb.2020.08.001","article-title":"Effects of intestinal luminal contents and the importance of microfold cells on the ability of cell-penetrating peptides to enhance epithelial permeation of insulin","volume":"155","author":"Kamei","year":"2020","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"10.1016\/j.jconrel.2021.07.030_bb0235","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1042\/bj20030760","article-title":"Passage of cell-penetrating peptides across a human epithelial cell layer in vitro","volume":"377","author":"Lindgren","year":"2004","journal-title":"Biochem. J."}],"container-title":["Journal of Controlled Release"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365921003734?httpAccept=text\/xml","content-type":"text\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/api.elsevier.com\/content\/article\/PII:S0168365921003734?httpAccept=text\/plain","content-type":"text\/plain","content-version":"vor","intended-application":"text-mining"}],"deposited":{"date-parts":[[2025,9,29]],"date-time":"2025-09-29T15:59:16Z","timestamp":1759161556000},"score":1,"resource":{"primary":{"URL":"https:\/\/linkinghub.elsevier.com\/retrieve\/pii\/S0168365921003734"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10]]},"references-count":47,"alternative-id":["S0168365921003734"],"URL":"https:\/\/doi.org\/10.1016\/j.jconrel.2021.07.030","relation":{},"ISSN":["0168-3659"],"issn-type":[{"value":"0168-3659","type":"print"}],"subject":[],"published":{"date-parts":[[2021,10]]},"assertion":[{"value":"Elsevier","name":"publisher","label":"This article is maintained by"},{"value":"Revealing the importance of carrier-cargo association in delivery of insulin and lipidated insulin","name":"articletitle","label":"Article Title"},{"value":"Journal of Controlled Release","name":"journaltitle","label":"Journal Title"},{"value":"https:\/\/doi.org\/10.1016\/j.jconrel.2021.07.030","name":"articlelink","label":"CrossRef DOI link to publisher maintained version"},{"value":"article","name":"content_type","label":"Content Type"},{"value":"\u00a9 2021 The Authors. Published by Elsevier B.V.","name":"copyright","label":"Copyright"}]}}